ENIntractable & Rare Diseases Research | Clinical and genetic characterization reveals a novel clinical classification for late-onset cobalamin C deficiency
日期: April 05, 2025
分类: Frontiers
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This study is the first to establish a symptom-based classification system for late-onset cobalamin C deficiency (LCCD) in the Northern Chinese population, identifying six distinct phenotypes and their genotype-phenotype correlations. It reveals that c.482G>A and c.80G>A variants are significantly associated with different clinical manifestations. Elevated total homocysteine (tHcy) levels serve as a key biomarker for neuropsychiatric and renal involvement. The findings provide critical insights for early diagnosis and personalized treatment of LCCD.
Literature Overview
The article Clinical and genetic characterization reveals a novel clinical classification for late-onset cobalamin C deficiency, published in the Intractable & Rare Diseases Research journal, reviews and summarizes the clinical and genetic features of 156 LCCD patients in Northern China. Through a multicenter retrospective analysis, the study proposes a six-phenotype classification system based on initial symptoms and explores the correlations between MMACHC variants and clinical presentations. It identifies that elevated tHcy levels are significantly associated with neuropsychiatric abnormalities, renal damage, and anemia. The study also highlights that different genotypes influence the age of onset and organ involvement patterns. Diagnostic delay is pointed out as a key contributor to poor prognosis, emphasizing the importance of early intervention.
Background Knowledge
Cobalamin C (cblC) deficiency is a rare autosomal recessive disorder caused by mutations in the MMACHC gene, leading to impaired vitamin B12 metabolism. It affects the synthesis of adenosylcobalamin and methylcobalamin, resulting in methylmalonic aciduria (MMA) and hyperhomocysteinemia. Clinical manifestations are highly heterogeneous, including neuropsychiatric abnormalities, myelopathy, renal dysfunction, among others, with age of onset ranging from infancy to adulthood. Due to its variable presentation, LCCD is frequently misdiagnosed, making it crucial to define its clinical and genetic features for accurate diagnosis and treatment. Although cblC deficiency has been studied, genotype-phenotype correlations in late-onset cases remain limited. Currently, no standardized classification system exists, and clinical diagnosis mainly relies on biochemical markers such as tHcy, MMA, and C3/C2 ratio. This study presents a novel symptom-guided classification system and explores the impact of various MMACHC mutations on disease expression, providing more precise diagnostic references for clinical practice.
Research Methods and Experimental Design
The study enrolled 156 genetically confirmed LCCD patients from eight medical centers in Northern China between October 2012 and November 2023. Inclusion criteria: tHcy > 50 µmol/L, biallelic pathogenic MMACHC variants, and age at onset > 1 year. Patients with secondary HHcy or HHcy caused by other genetic conditions were excluded. Clinical, biochemical, neuroimaging, EEG, EMG, and genetic sequencing data were collected. Statistical analysis was performed using SPSS and GraphPad Prism. Continuous variables were expressed as median (IQR) and compared using Mann-Whitney U test due to non-normal distribution; categorical variables were expressed as frequency and percentage, and compared using Chi-square test or Fisher’s exact test (p < 0.05 considered statistically significant).
Key Findings and Insights
Significance and Future Directions
This study provides a new classification system for LCCD, aiding clinicians in identifying distinct phenotypes and implementing tailored treatment strategies. Future research should validate the classification in other populations and explore precision treatment approaches based on genotypes. Developing user-friendly tools for tHcy monitoring and improving treatment adherence can also enhance patient outcomes. Investigations into gene therapy and cell-based interventions, such as cblC mouse models, may offer novel therapeutic avenues for long-term management.
Conclusion
This study systematically analyzed the clinical and genetic features of late-onset cobalamin C deficiency (LCCD) in the Northern Chinese population for the first time, proposing a six-subtype classification system based on initial symptoms and identifying correlations between MMACHC variants and clinical phenotypes. The c.482G>A mutation is associated with milder phenotypes and spastic paraplegia, whereas c.80G>A is linked to early-onset and renal or pulmonary complications. Elevated tHcy levels serve as a key biomarker for neuropsychiatric abnormalities, renal damage, and anemia. Although treatment protocols are similar among patients, poor adherence remains a major cause of recurrence and poor outcomes. The study emphasizes the importance of early diagnosis and individualized management, offering critical guidance for clinical practice in LCCD.
